PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is a health burden worldwide that is highly prevalent and deadly but also preventable. African Americans (AAs) suffer disproportionately from CRC in the US, and biological factors underlying these disparities remain understudied. Environmental exposures, such as active vitamin D ( 1?,25(OH)2D3) , interact with normal colon to modify CRC development. If we could understand how these interactions differ between individuals or populations, they could be harnessed to identify those at highest CRC risk and potentially identify new ways to prevent this cancer. Until now, traditional models could not study host-environment interactions between individuals in human colon. To address this gap, we have established an experimental framework that uses primary ex vivo colon culture and human organoid culture to study inter-individual and inter-ethnic differences in responses to environmental exposures. Our initial work has identified a promising candidate, uridine phosphorylase 1 (UPP1), a key enzyme of uridine homeostasis and pyrimidine salvage that showed significant inter-ethnic differences in transcriptional response to 1?,25(OH)2D3. A knock out mouse of uridine phosphorylase led to spontaneous colon tumors due to DNA damage providing rationale for studying this candidate in the context of CRC disparities. In this exploratory study, we will test the hypothesis that 1?,25(OH)2D3 regulates uridine homeostasis and DNA damage in the colon, and that this regulation differs between populations (Aim 1). Having found that our experimental framework is productive and promising, we will extend it to identify inter-ethnic differences in gene expression and in chromatin accessibility in response to vitamin D with greater power compared to our preliminary study (Aim 2). Ultimately, this exploratory work is the basis for larger, comprehensive studies of inter-individual and inter-ethnic host-environment interactions in CRC susceptibility. In an era where the need for precision medicine at the individual and population level is recognized, our studies will determine how 1?,25(OH)2D3 responses differ across populations that eventually might lead to personalized vitamin D-based interventions for CRC prevention especially in AAs.